1Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Abstract

Levels of kynurenic acid (KYNA), an endogenous product of tryptophan degradation, are elevated in the brain and cerebrospinal fluid of individuals with schizophrenia (SZ). This increase has been implicated in the cognitive dysfunctions seen in the disease, as KYNA is an antagonist of the α7 nicotinic acetylcholine receptor and the N-methyl-d-aspartate receptor, both of which are critically involved in cognitive processes and in a defining neurodevelopmental period in the pathophysiology of SZ. We tested the hypothesis that early developmental increases in brain KYNA synthesis might cause biochemical and functional impairments in adulthood. To this end, we stimulated KYNA formation by adding the KYNA precursor kynurenine (100 mg/day) to the chow fed to rat dams from gestational day 15 to postnatal day 21 (PD 21). This treatment raised brain KYNA levels in the offspring by 341% on PD 2 and 210% on PD 21. Rats were then fed normal chow until adulthood (PD 56-80). In the adult animals, basal levels of extracellular KYNA, measured in the hippocampus by in vivo microdialysis, were elevated (+12%), whereas extracellular glutamate levels were significantly reduced (-13%). In separate adult animals, early kynurenine treatment was shown to impair performance in two behavioral tasks linked to hippocampal function, the passive avoidance test and the Morris water maze test. Collectively, these studies introduce a novel, naturalistic rat model of SZ, and also suggest that increases in brain KYNA during a vulnerable period in brain development may play a significant role in the pathophysiology of the disease.

Kynurenine-treated dams were fed a diet of wet rodent chow mash supplemented with 100 mg kynurenine per animal per day from GD 15 until PD 21. On PD 21, offspring were weaned from their mothers and pair-housed until adulthood. Biochemical and behavioral studies were performed in adulthood, as indicated.

Exposure to kynurenine (100 mg/day) from GD 15 until weaning raised kynurenine levels in the serum of both mothers (A) and pups (B) on PD 21. Data are the mean ± SEM (n = 10 per group for dams; n = 8 per group for offspring). *** P < 0.001 vs. control.

Pre- and postnatal kynurenine treatment does not affect tissue levels of KYNA and 3-HK in the hippocampus in adulthood

Rats were exposed to kynurenine (100 mg/day) from GD 15 until weaning, and kynurenine pathway metabolites were determined in hippocampal tissue of animals that were euthanized during adulthood (PD 56-80). Levels of KYNA (A) and 3-HK (B) did not differ significantly between controls and kynurenine-treated rats (P > 0.05). Data are the mean ± SEM (n = 9 per group).

Animals exposed to kynurenine during pre- and early postnatal development show contextual memory impairment in adulthood

Rats were exposed to kynurenine (100 mg/day) from GD 15 until weaning and were tested in the passive avoidance paradigm during adulthood (PD 56-80; n = 12 per group). No differences in approach latency were observed on the training day (A), but avoidance latency differed significantly between the two groups 24 h later (B). All data are the mean ± SEM. *** P < 0.001 vs. control.

Spatial learning and reference memory is impaired in animals receiving kynurenine during pre- and early postnatal development

Rats were exposed to kynurenine (100 mg/day) from GD 15 until weaning and were tested in the MWM during adulthood (PD 56- 80; n = 12 per group). A) Test across 6 days of training; B) Number of platform crossings during the probe trial (video tracking analysis); C) Percent of time spent in the target quadrant during the probe trial (video tracking analysis). All data are the mean ± SEM. * P < 0.05 and ** P < 0.01 vs. control.